Freeze drying or lyophilisation is a well known method for stabilization of otherwise easily degradable material, such as micro-organisms, food items, biological products and pharmaceuticals. In the field of pharmaceuticals, freeze drying is for example used in the production of injectable dosage forms, diagnostics, and oral solid dosage forms. Freeze drying is also suited for aseptic treatment of a material, since the material can be handled at sterile conditions until it is freeze dried into the final product.
A conventional freeze-drying apparatus, such as the one disclosed in U.S. Pat. No. 4,612,200, comprises a vacuum chamber in which the material to be freeze dried is placed. The apparatus also comprises heater means, such as IR heaters irradiating the material in the chamber, and pump/valve means controlling the pressure in the chamber. During the freeze-drying process, the temperature of the material is monitored by thermocouples arranged in contact with the material, which is distributed in samples within the vacuum chamber. This approach has certain drawbacks. First, the thermocouple will act as a site for heterogeneous nucleation and thereby influence the freezing behavior, resulting in different ice structure and subsequent drying behavior between monitored and non-monitored samples. Relative to the monitored samples, the non-monitored samples will also have a somewhat lower temperature and demand a different drying time. Second, the use of thermocouples in contact with the material is unsuitable for aseptic processing. Third, automatic loading and unloading of the material in the vacuum chamber might be difficult, since the thermocouples must be inserted physically into the material.
It also known to monitor the moisture content in the vacuum chamber during the freeze-drying process. In the article “Moisture measurement: A new method for monitoring freeze-drying cycles” by Bardat et al, published in the Journal of Parenteral Science and Technology, No 6, pp 293-299, the moisture content in the vacuum chamber is measured by means of one or more pressure gauges or a hygrometer. In the article “Monitor lyophilization with mass spectrometer gas analysis” by Connelly et al, published in the Journal of Parenteral Science and Technology, No 2, pp 70-75, the moisture content in the vacuum chamber is measured by means of a mass spectrometer. These prior art techniques are indirect and as such capable of identifying a suitable overall end point of the freeze-drying process, but the moisture content of the material itself cannot be readily assessed during the freeze-drying process. Further, the relationship between measurement response and actual moisture content of the material has to be established empirically for each type of material and freeze-drying apparatus, which is a laborious task in production scale. Also, these indirect measurements require a low and constant leak rate of the vacuum chamber, necessitating frequent leak rate tests. This is a particular problem when high-temperature sterilization is employed inside the vacuum chamber, for example by means of steam treatment, since it is common for the high sterilization temperatures to cause leaks.